The natural product FR901464, isolated from the broth of a Pseudomonas sp. No. 2663 culture, is a transcriptional activator. It lowers the mRNA levels of p53, p21, c-myc, and E2F-1 in MCF-7 cells at 20 nM, and it induces apparent apoptosis in MCF-7 cells with the impressive LC50 of 0.5 nM. FR901464 also exhibits an antitumor activity in a mouse model at remarkably low concentrations (0.056-0.18 mg/kg).
This pharmacological profile for FR901464 has drawn considerable interest, focusing on its potential as an anticancer agent. A 4-TEGylated-FR901464 analog, depicted below, has been prepared and found to have a high cancer cell antiproliferative activity.

Additionally, the right fragment of the 4-TEGylated-FR901464 analog, depicted below, was found to exhibit high cancer cell antiproliferative activity.

The preparation of more potent analogs has been limited by a lengthy synthesis involving at least nineteen linear steps and typically forty or more in total. Accordingly, the present invention provides novel analogs of FR901464, as well as new and improved methods for preparing FR901464 and its analogs.